Marine litter is a global challenge and society plays an important role via lifestyles and behaviour, including policy support. We analysed public perceptions of marine litter and contributing ...factors, using data from 1133 respondents across 16 European countries. People reported high levels of concern about marine litter, and the vast majority (95%) reported seeing litter when visiting the coast. The problem was attributed to product and packaging design and behaviour rather than lack of facilities or accidental loss of items. Retailers, industry and government were perceived as most responsible, but also least motivated and competent to reduce marine litter, whereas scientists and environmental groups were perceived as least responsible but most motivated and competent. Regression analyses demonstrated the importance of psychological factors such as values and social norms above sociodemographic variables. These findings are important for communications and interventions to reduce inputs of marine litter to the natural environment.
•Public perceptions play an important role when devising interventions to reduce marine litter.•This paper analysed over 1000 public survey responses from 16 European countries.•Respondents reported high concern and over 95% of them reported seeing litter when visiting the coast.•Marine litter was attributed to product and packaging design.•Perceived responsibility, motivation and competence of different stakeholders were compared.•Values and norms were more highly associated with concern and behavioural intentions than were sociodemographic variables.
•We evaluated a marine litter educational activity for children.•At baseline, children showed a degree of understanding about causes and impacts.•After the activity, concern and understanding of the ...causes and impacts increased.•Report engaging in more actions to reduce the potential causes of marine litter.
Marine litter is a significant environmental problem inherently linked to individuals’ purchasing, use and disposal behaviour. This research examined 176 British schoolchildren’s (aged 8–13years) baseline marine litter understanding and self-reported actions, and tested the impact of an educational intervention. All children participated in the educational intervention and completed a pre- and post-intervention questionnaire. At baseline, children were quite concerned about marine litter and recognised some of the causes and impacts of the problem. Children also reported taking a number of actions to help solve the problem. After the intervention, children were significantly more concerned, had a better understanding of the causes and negative impacts, and reported engaging in more actions to reduce the potential causes of marine litter. Understanding the perceptions and behaviours of children is crucial as they represent current and future actors and a potentially important source of social influence among their peers, parents and community.
Mitochondrial function is central to a wide range of biological processes in health and disease and there is considerable interest in developing small molecules that are taken up by mitochondria and ...act as either probes of mitochondrial function or therapeutics in vivo.
Various strategies have been used to target small molecules to mitochondria, particularly conjugation to lipophilic cations and peptides, and most of the work so far has been on mitochondria-targeted antioxidants and redox probes. In vivo studies will reveal whether there are differences in the types of bioactive functionalities that can be delivered using different carriers.
The outstanding challenge in the area is to discover how to combine the established selective delivery to mitochondria with the specific delivery to particular organs.
These targeting methods will be used to direct many other bioactive molecules to mitochondria and many more wider applications other than just to antioxidants can be anticipated in the future.
The mitochondrial electron transport chain is a major source of reactive oxygen species (ROS) and is also a target of ROS, with an implied role in the stabilization of hypoxia-inducible factor (HIF) ...and induction of the AMPK pathway. Here we used varying doses of two agents, Mito-Paraquat and Mito-Metformin, that have been conjugated to cationic triphenylphosphonium (TPP+) moiety to selectively target them to the mitochondrial matrix compartment, thereby resulting in the site-specific generation of ROS within mitochondria. These agents primarily induce superoxide (O2•–) production by acting on complex I. In Raw264.7 macrophages, C2C12 skeletal myocytes, and HCT116 adenocarcinoma cells, we show that mitochondria-targeted oxidants can induce ROS (O2•– and H2O2). In all three cell lines tested, the mitochondria-targeted agents disrupted membrane potential and activated calcineurin and the Cn-dependent retrograde signaling pathway. Hypoxic culture conditions also induced Cn activation and HIF1α activation in a temporally regulated manner, with the former appearing at shorter exposure times. Together, our results indicate that mitochondrial oxidant-induced retrograde signaling is driven by disruption of membrane potential and activation of Ca2+/Cn pathway and is independent of ROS-induced HIF1α or AMPK pathways.
•Mitochondrial ROS (O2.•–, H2O2) induce a stress signaling pathway implicated in many diseases.•Mitochondrial ROS induce the Ca2+/Cn pathway in addition to HIF1α and AMPK pathways.•Mitochondria-targeted agents MitoPQ and MitoMet induce the Ca2+/Cn and AMPK pathways.•Inhibition of complex III by Antimycin A also activates the Ca2+/Cn and AMPK pathways but not HIF1α.•The three pathways appear to require different thresholds of mitochondrial ROS.
Coenzyme Q (CoQ) is an essential cofactor, primarily found in the mitochondrial inner membrane where it functions as an electron carrier in the respiratory chain, and as a lipophilic antioxidant. The ...redox state of the CoQ pool is the ratio of its oxidised (ubiquinone) and reduced (ubiquinol) forms, and is a key indicator of mitochondrial bioenergetic and antioxidant status. However, the role of CoQ redox state in vivo is poorly understood, because determining its value is technically challenging due to redox changes during isolation, extraction and analysis. To address these problems, we have developed a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay that enables us to extract and analyse both the CoQ redox state and the magnitude of the CoQ pool with negligible changes to redox state from small amounts of tissue. This will enable the physiological and pathophysiological roles of the CoQ redox state to be investigated in vivo.
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•Sensitive LC-MS/MS assay to quantify CoQ redox state.•Changes in CoQ redox state can be measured in mitochondria, cells and in vivo.•CoQ redox state is stable during extraction and analysis.
Hydrogen peroxide (H2O2) is central to mitochondrial oxidative damage and redox signaling, but its roles are poorly understood due to the difficulty of measuring mitochondrial H2O2 in vivo. Here we ...report a ratiometric mass spectrometry probe approach to assess mitochondrial matrix H2O2 levels in vivo. The probe, MitoB, comprises a triphenylphosphonium (TPP) cation driving its accumulation within mitochondria, conjugated to an arylboronic acid that reacts with H2O2 to form a phenol, MitoP. Quantifying the MitoP/MitoB ratio by liquid chromatography-tandem mass spectrometry enabled measurement of a weighted average of mitochondrial H2O2 that predominantly reports on thoracic muscle mitochondria within living flies. There was an increase in mitochondrial H2O2 with age in flies, which was not coordinately altered by interventions that modulated life span. Our findings provide approaches to investigate mitochondrial ROS in vivo and suggest that while an increase in overall mitochondrial H2O2 correlates with aging, it may not be causative.
► A mitochondria-targeted mass spectrometry probe measures mitochondrial H2O2 in vivo ► Overall mitochondrial H2O2 increases with age but can be independent of life span ► Increased physical activity leads to a decrease in mitochondrial H2O2 ► Hypotheses dependent on overall mitochondrial ROS can now be assessed in vivo
Mitochondrial pharmacology Smith, Robin A.J; Hartley, Richard C; Cochemé, Helena M ...
Trends in pharmacological sciences (Regular ed.),
06/2012, Letnik:
33, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Mitochondria are being recognized as key factors in many unexpected areas of biomedical science. In addition to their well-known roles in oxidative phosphorylation and metabolism, it is now clear ...that mitochondria are also central to cell death, neoplasia, cell differentiation, the innate immune system, oxygen and hypoxia sensing, and calcium metabolism. Disruption to these processes contributes to a range of human pathologies, making mitochondria a potentially important, but currently seemingly neglected, therapeutic target. Mitochondrial dysfunction is often associated with oxidative damage, calcium dyshomeostasis, defective ATP synthesis, or induction of the permeability transition pore. Consequently, therapies designed to prevent these types of damage are beneficial and can be used to treat many diverse and apparently unrelated indications. Here we outline the biological properties that make mitochondria important determinants of health and disease, and describe the pharmacological strategies being developed to address mitochondrial dysfunction.
Vascular Nox (NADPH oxidase)-derived reactive oxygen species and endoplasmic reticulum (ER) stress have been implicated in hypertension. However, relationships between these processes are unclear. We ...hypothesized that Nox isoforms localize in a subcellular compartment-specific manner, contributing to oxidative and ER stress, which influence the oxidative proteome and vascular function in hypertension. Nox compartmentalization (cell fractionation), O
(lucigenin), H
O
(amplex red), reversible protein oxidation (sulfenylation), irreversible protein oxidation (protein tyrosine phosphatase, peroxiredoxin oxidation), and ER stress (PERK protein kinase RNA-like endoplasmic reticulum kinase, IRE1α inositol-requiring enzyme 1, and phosphorylation/oxidation) were studied in spontaneously hypertensive rat (SHR) vascular smooth muscle cells (VSMCs). VSMC proliferation was measured by fluorescence-activated cell sorting, and vascular reactivity assessed in stroke-prone SHR arteries by myography. Noxs were downregulated by short interfering RNA and pharmacologically. In SHR, Noxs were localized in specific subcellular regions: Nox1 in plasma membrane and Nox4 in ER. In SHR, oxidative stress was associated with increased protein sulfenylation and hyperoxidation of protein tyrosine phosphatases and peroxiredoxins. Inhibition of Nox1 (NoxA1ds), Nox1/4 (GKT137831), and ER stress (4-phenylbutyric acid/tauroursodeoxycholic acid) normalized SHR vascular reactive oxygen species generation. GKT137831 reduced IRE1α sulfenylation and XBP1 (X-box binding protein 1) splicing in SHR. Increased VSMC proliferation in SHR was normalized by GKT137831, 4-phenylbutyric acid, and STF083010 (IRE1-XBP1 disruptor). Hypercontractility in the stroke-prone SHR was attenuated by 4-phenylbutyric acid. We demonstrate that protein hyperoxidation in hypertension is associated with oxidative and ER stress through upregulation of plasmalemmal-Nox1 and ER-Nox4. The IRE1-XBP1 pathway of the ER stress response is regulated by Nox4/reactive oxygen species and plays a role in the hyperproliferative VSMC phenotype in SHR. Our study highlights the importance of Nox subcellular compartmentalization and interplay between cytoplasmic reactive oxygen species and ER stress response, which contribute to the VSMC oxidative proteome and vascular dysfunction in hypertension.
The increased expression of genes induced by type I interferon (IFN) is characteristic of viral infections and systemic lupus erythematosus (SLE). We showed that mitochondrial antiviral signaling ...(MAVS) protein, which normally forms a complex with retinoic acid gene I (RIG-I)-like helicases during viral infection, was activated by oxidative stress independently of RIG-I helicases. We found that chemically generated oxidative stress stimulated the formation of MAVS oligomers, which led to mitochondrial hyperpolarization and decreased adenosine triphosphate production and spare respiratory capacity, responses that were not observed in similarly treated cells lacking MAVS. Peripheral blood lymphocytes of SLE patients also showed spontaneous MAVS oligomerization that correlated with the increased secretion of type I IFN and mitochondrial oxidative stress. Furthermore, inhibition of mitochondrial reactive oxygen species (ROS) by the mitochondria-targeted antioxidant MitoQ prevented MAVS oligomerization and type I IFN production. ROS-dependent MAVS oligomerization and type I IFN production were reduced in cells expressing the MAVS-C79F variant, which occurs in 30% of sub-Saharan Africans and is linked with reduced type I IFN secretion and milder disease in SLE patients. Patients expressing the MAVS-C79F variant also had reduced amounts of oligomerized MAVS in their plasma compared to healthy controls. Together, our findings suggest that oxidative stress-induced MAVS oligomerization in SLE patients may contribute to the type I IFN signature that is characteristic of this syndrome.
Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic ...tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies.
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